One of the main ways that alcohol causes health problems is by its actions on the hypothalamus-pituitary-adrenal (HPA) or "stress" axis. Interestingly, the HPA axes of males and females respond differently to stressors and to drugs like alcohol. The general hypothesis for the research proposed in this grant is that gonadal hormones such as estrogen and testosterone alter neuronal responsiveness to alcohol, resulting in sexually dimorphic HPA axis function. The longterm objective of the work is to elucidate the anatomical and functional neuronal machinery underlying sex- specific HPA responses to alcohol in rats. Increasing our understanding of the mechanisms responsible for sexually dimorphic HPA responses is imperative if gender- specific treatments for medical problems that arise with alcohol use and abuse are to be created. In order to highlight the role of the CNS in HPA activation by alcohol, the proposed experiments will use the relatively novel alcohol delivery method of microinfusing a modest amount of the drug directly into the cerebroventricular systems (icv administration) of rats. Alcohol administered in this manner does not cause neuronal damage and does not leak to the periphery in measurable amounts, but has highly explicit actions on the CNS. This model simplifies the study of strictly brain- mediated sex differences in HPA responses to alcohol by obviating the noxious peripheral actions of the drug that feed back to the brain and alter its function in a non-specific manner. Such feedback dramatically increases HPA activity, and tremendously complicates the study of sex differences in HPA responses to alcohol. Studies for Specific Aim 1 will investigate the mechanisms underlying sex differences in HPA- linked neuronal responses to alcohol administration. This work will first focus on identifying specific brain regions responsive to alcohol, involved in the regulation of the HPA axis, and sensitive to gonadal hormones. We will then probe the functional roles of specific gonadal hormones and their receptors in regulating neuronal activation relevant to HPA function. Studies for Specific Aim 2 will investigate the mechanisms by which gonadal steroids and their receptors interact to cause sex- dependent secretion of stresslinked hormones following icv alcohol administration. Overall, this research will elucidate the neuroanatomical loci and hormone receptor machinery responsible for sex- specific HPA responses to alcohol. This information can then be used to develop sex- related treatments for alcohol- related health problems.